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Russell L. Margolis - One of the best experts on this subject based on the ideXlab platform.
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Spinocerebellar ataxia type 12: clues to pathogenesis.
Current opinion in neurology, 2016Co-Authors: Rachael L. Cohen, Russell L. MargolisAbstract:Purpose of reviewSpinocerebellar ataxia type 12 (SCA12) is a rare autosomal dominant neurodegenerative disease characterized by tremor, gait abnormalities, and neuropsychiatric syndromes. The location of the causative CAG/CTG expansion mutation in PPP2R2B, a gene encoding regulatory units of the pro
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Spinocerebellar Ataxia Type 12
Handbook of clinical neurology, 2012Co-Authors: Elizabeth O'hearn, Susan E. Holmes, Russell L. MargolisAbstract:SCA12 is a late-onset, autosomal dominant, slowly progressive disorder. Action tremor is the usual presenting sign. Subsequent development of ataxia and hyperreflexia suggests spinocerebellar ataxia. In the index SCA12 kindred, which resides in North America and is of German ancestry, parkinsonism, anxiety, depression, and cognitive dysfunction are not uncommon. SCA12 is linked to a CAG repeat expansion mutation in exon 7 of PPP2R2B, a gene that encodes Bβ, a regulatory subunit of protein phosphatase 2A (PP2A). CAG repeats number 7-28 in normal individuals and 55-78 in SCA12 patients. The mechanism by which this mutation leads to SCA12 has not been determined. The CAG expansion in PPP2R2B has promoter function in vitro. CAG length correlates with increased Bβ expression. There is no evidence that this CAG expansion results in polyglutamine production. In addition to the North. American SCA12 kindred, multiple SCA12 families have been found in Northern India that are not related to the index SCA12 kindred. SCA12 has been reported, rarely, in Singapore and China. Action tremor, anxiety, and depression in SCA12 have responded to usual treatments for these disorders. SCA12 may be considered in patients who present with action tremor and later develop signs of cerebellar and cortical dysfunction.
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Genetic Instabilities and Neurological Diseases (Second Edition) - CHAPTER 31 – Spinocerebellar Ataxia Type 12
Genetic Instabilities and Neurological Diseases, 2006Co-Authors: Susan E. Holmes, Elizabeth O'hearn, Hyon S. Hwang, Christopher A. Ross, Natividad Cortez-apreza, S. Strack, Russell L. MargolisAbstract:This chapter focuses on spinocerebellar ataxia type 12 (SCA12) caused by a CAG repeat expansion in PPP2R2 that encodes one of the brain-specific regulatory subunits of the trimeric phosphatase PP2A. SCA12 is the second most common SCA in India, accounting for approximately 8% of dominant ataxia cases; however, it is a rare disease in all other populations studied to date, having been found in only the single North American index pedigree. Clinically, SCA12 is the only inherited SCA that has action tremor as the presenting and most common sign. The SCA12 CAG repeat is found in the probable promoter region of the PPP2R2B variant encoding the predominant isoform (Bβ1) of the Bβ regulatory subunit. Repeat expansion appears to drive increased transcription from this promoter, suggesting that disease pathogenesis may involve overexpression of Bβ1 and lead to altered activity of PP2A, a ubiquitous enzyme implicated in multiple cellular processes including apoptosis. The SCA12 repeat is also within the intronic sequence of multiple alternately spliced transcripts with alternate promoters that encode additional Bβ isoforms, including Bβ2, which targets PP2A to the mitochondria, and promotes apoptosis when overexpressed. Pathogenesis may also involve an expansion-induced shift in splicing or choice of promoters, leading to an increase in expression of Bβ2.
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Evidence of a Common Founder for SCA12 in the Indian Population
Annals of Human Genetics, 2005Co-Authors: Samira Bahl, Elizabeth O'hearn, Susan E. Holmes, Russell L. Margolis, K. Virdi, Uma Mittal, Mohinder Pal Sachdeva, A.k. Kalla, S. Jain, Achal K. SrivastavaAbstract:Spinocerebellar ataxia type 12 (SCA12) is an autosomal dominant cerebellar ataxia associated with the expansion of an unstable CAG repeat in the 5' region of the PPP2R2B gene on chromosome 5q31-5q32. We found that it accounts for approximately 16% (20/124) of all the autosomal dominant ataxia cases diagnosed in AIIMS, a major tertiary referral centre in North India. The length of the expanded allele in this population ranges from 51-69 CAG triplets. Interestingly, all the affected families belong to an endogamous population, which originated in the state of Haryana, India. We identified four novel SNPs and a dinucleotide marker spanning approximately 137 kb downstream of CAG repeat in the PPP2R2B gene. Analysis of 20 Indian SCA12 families and ethnically matched normal unrelated individuals revealed one haplotype to be significantly associated with the affected alleles (P= 0.000), clearly indicating the presence of a common founder for SCA12 in the Indian population. This haplotype was not shared by the American pedigree with SCA12. Therefore, the SCA12 expansion appears to have originated at least twice.
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Spinocerebellar Ataxia 12 (SCA12)
Genetics of Movement Disorders, 2003Co-Authors: Susan E. Holmes, Elizabeth O'hearn, Christopher A. Ross, Samir K. Brahmachari, Shweta Choudhry, Achal K. Srivastava, Satish Jain, Russell L. MargolisAbstract:Publisher Summary Spinocerebellar ataxia type 12 (SCA12) is an autosomal dominant neurodegenerative disorder that is described in the pedigrees of German-American and Indian descent. The phenotype typically begins with tremor in the fourth decade, progressing to include ataxia and other cerebellar and cortical signs. SCA12 is associated with an expansion of a CAG repeat in the 5' region of the gene PPP2R2B, which encodes a brain-specific regulatory sub unit of the protein phosphatase PP2A. The repeat size ranges from 55–78 triplets in the mutant allele of affected individuals, and from 7–31 triplets in normal alleles. It is possible that an expansion mutation in PPP2R2B may influence PPP2R2B expression, perhaps altering the activity of PP2A, an enzyme implicated in multiple cellular functions, including cell cycle regulation, tau phosphorylation, and apoptosis. They cannot usually be distinguished based on clinical features alone, but 16 distinct SCAs to date have been identified with the elucidation of the genetic basis for each. Therapy for essential tremor is helpful in some cases. Psychiatric symptoms, which may cause significant morbidity in SCA12 and other SCAs, are successfully managed in SCA12 with anxiolytic and antidepressant medicines. Other palliative treatments, including social support, physical therapy, and occupational therapy help maximize patient functional capacity.
Susan E. Holmes - One of the best experts on this subject based on the ideXlab platform.
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Neuropathology and Cellular Pathogenesis of Spinocerebellar Ataxia Type 12.
Movement disorders : official journal of the Movement Disorder Society, 2015Co-Authors: Elizabeth O'hearn, Hyon S. Hwang, Susan E. Holmes, Dobrila D. Rudnicki, Daniel W. Chung, Ana I. Seixas, Rachael L. Cohen, Christopher A. Ross, John Q. Trojanowski, Olga PletnikovaAbstract:Objective SCA12 is a progressive autosomal-dominant disorder, caused by a CAG/CTG repeat expansion in PPP2R2B on chromosome 5q32, and characterized by tremor, gait ataxia, hyperreflexia, dysmetria, abnormal eye movements, anxiety, depression, and sometimes cognitive impairment. Neuroimaging has demonstrated cerebellar and cortical atrophy. We now present the neuropathology of the first autopsied SCA12 brain and utilize cell models to characterize potential mechanisms of SCA12 neurodegeneration. Methods A fixed SCA12 brain was examined using gross, microscopic, and immunohistochemical methods. The effect of the repeat expansion on PPP2R2B Bβ1 expression was examined in multiple cell types by transient transfection of constructs containing the PPP2R2B Bβ1 promoter region attached to a luciferase reporter. The neurotoxic effect of PPP2R2B overexpression was examined in transfected rat primary neurons. Results Neuropathological investigation revealed enlarged ventricles, marked cerebral cortical atrophy and Purkinje cell loss, less-prominent cerebellar and pontine atrophy, and neuronal intranuclear ubiquitin-positive inclusions, consistent with Marinesco bodies, which did not stain for long polyglutamine tracts, alpha-synuclein, tau, or transactive response DNA-binding protein 43. Reporter assays demonstrated that the region of PPP2R2B containing the repeat functions as a promoter, and that promoter activity increases with longer repeat length and is dependent on cell type, repeat sequence, and sequence flanking the repeat. Overexpression of PPP2R2B in primary cortical neurons disrupted normal morphology. Conclusions SCA12 involves extensive, but selective, neurodegeneration distinct from Alzheimer's disease, synucleinopathies, tauopathies, and glutamine expansion diseases. SCA12 neuropathology may arise from the neurotoxic effect of repeat-expansion–induced overexpression of PPP2R2B. © 2015 International Parkinson and Movement Disorder Society
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Spinocerebellar Ataxia Type 12
Handbook of clinical neurology, 2012Co-Authors: Elizabeth O'hearn, Susan E. Holmes, Russell L. MargolisAbstract:SCA12 is a late-onset, autosomal dominant, slowly progressive disorder. Action tremor is the usual presenting sign. Subsequent development of ataxia and hyperreflexia suggests spinocerebellar ataxia. In the index SCA12 kindred, which resides in North America and is of German ancestry, parkinsonism, anxiety, depression, and cognitive dysfunction are not uncommon. SCA12 is linked to a CAG repeat expansion mutation in exon 7 of PPP2R2B, a gene that encodes Bβ, a regulatory subunit of protein phosphatase 2A (PP2A). CAG repeats number 7-28 in normal individuals and 55-78 in SCA12 patients. The mechanism by which this mutation leads to SCA12 has not been determined. The CAG expansion in PPP2R2B has promoter function in vitro. CAG length correlates with increased Bβ expression. There is no evidence that this CAG expansion results in polyglutamine production. In addition to the North. American SCA12 kindred, multiple SCA12 families have been found in Northern India that are not related to the index SCA12 kindred. SCA12 has been reported, rarely, in Singapore and China. Action tremor, anxiety, and depression in SCA12 have responded to usual treatments for these disorders. SCA12 may be considered in patients who present with action tremor and later develop signs of cerebellar and cortical dysfunction.
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Genetic Instabilities and Neurological Diseases (Second Edition) - CHAPTER 31 – Spinocerebellar Ataxia Type 12
Genetic Instabilities and Neurological Diseases, 2006Co-Authors: Susan E. Holmes, Elizabeth O'hearn, Hyon S. Hwang, Christopher A. Ross, Natividad Cortez-apreza, S. Strack, Russell L. MargolisAbstract:This chapter focuses on spinocerebellar ataxia type 12 (SCA12) caused by a CAG repeat expansion in PPP2R2 that encodes one of the brain-specific regulatory subunits of the trimeric phosphatase PP2A. SCA12 is the second most common SCA in India, accounting for approximately 8% of dominant ataxia cases; however, it is a rare disease in all other populations studied to date, having been found in only the single North American index pedigree. Clinically, SCA12 is the only inherited SCA that has action tremor as the presenting and most common sign. The SCA12 CAG repeat is found in the probable promoter region of the PPP2R2B variant encoding the predominant isoform (Bβ1) of the Bβ regulatory subunit. Repeat expansion appears to drive increased transcription from this promoter, suggesting that disease pathogenesis may involve overexpression of Bβ1 and lead to altered activity of PP2A, a ubiquitous enzyme implicated in multiple cellular processes including apoptosis. The SCA12 repeat is also within the intronic sequence of multiple alternately spliced transcripts with alternate promoters that encode additional Bβ isoforms, including Bβ2, which targets PP2A to the mitochondria, and promotes apoptosis when overexpressed. Pathogenesis may also involve an expansion-induced shift in splicing or choice of promoters, leading to an increase in expression of Bβ2.
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Evidence of a Common Founder for SCA12 in the Indian Population
Annals of Human Genetics, 2005Co-Authors: Samira Bahl, Elizabeth O'hearn, Susan E. Holmes, Russell L. Margolis, K. Virdi, Uma Mittal, Mohinder Pal Sachdeva, A.k. Kalla, S. Jain, Achal K. SrivastavaAbstract:Spinocerebellar ataxia type 12 (SCA12) is an autosomal dominant cerebellar ataxia associated with the expansion of an unstable CAG repeat in the 5' region of the PPP2R2B gene on chromosome 5q31-5q32. We found that it accounts for approximately 16% (20/124) of all the autosomal dominant ataxia cases diagnosed in AIIMS, a major tertiary referral centre in North India. The length of the expanded allele in this population ranges from 51-69 CAG triplets. Interestingly, all the affected families belong to an endogamous population, which originated in the state of Haryana, India. We identified four novel SNPs and a dinucleotide marker spanning approximately 137 kb downstream of CAG repeat in the PPP2R2B gene. Analysis of 20 Indian SCA12 families and ethnically matched normal unrelated individuals revealed one haplotype to be significantly associated with the affected alleles (P= 0.000), clearly indicating the presence of a common founder for SCA12 in the Indian population. This haplotype was not shared by the American pedigree with SCA12. Therefore, the SCA12 expansion appears to have originated at least twice.
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Why is SCA12 different from other SCAs
Cytogenetic and genome research, 2003Co-Authors: Susan E. Holmes, Elizabeth O'hearn, R L MargolisAbstract:Spinocerebellar ataxia type 12 (SCA12), now described in European-American and Asian (Indian) pedigrees, is unique among the SCAs from clinical, pathological, and molecular perspectives. Clinically, the distinguishing feature is early and prominent action tremor with variability in other signs. Pathologically, brain MRIs also suggest variability, with prominent cortical as well as cerebellar atrophy. Genetically, SCA12 is caused by a CAG repeat expansion that does not encode polyglutamine; we speculate that the mutation may affect expression of the gene PPP2R2B, which encodes a brain-specific regulatory subunit of the protein phosphatase PP2A.
Achal K. Srivastava - One of the best experts on this subject based on the ideXlab platform.
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Spinocerebellar ataxia type 12: An update
Annals of Movement Disorders, 2019Co-Authors: Deepak Kumar, Achal K. Srivastava, Mohammad Faruq, Varun R GundluruAbstract:Spinocerebellar ataxia type 12 (SCA12) is a progressive neurological disorder with a unique prevalence in North Indian population. Trinucleotide CAG repeat expansion beyond certain threshold (>43 repeats) in the upstream region of PPP2R2B gene is associated with cerebello-cortical atrophy in disease affected individuals. Patients with SCA12 predominantly manifest unique distinguishable feature of early slow and progressive action tremor in upper extremities followed by other variable symptoms such as mild to moderate gait ataxia, speech disturbances with tremulous voice, head tremor, and autonomic abnormalities. At present, there is no definite treatment available to cure this disease and the underlying disease mechanism at molecular level largely remains undetermined. This review focuses on epidemiology, clinico-genetic advancements, and therapeutics interventions emerged over the time in this field.
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transcriptomic dynamics of a non coding trinucleotide repeat expansion disorder sca12 in ipsc derived neuronal cells signatures of interferon induced response
bioRxiv, 2018Co-Authors: Deepak Kumar, Achal K. Srivastava, Ashaq Hussain, Mitali Mukerji, Odity Mukherjee, Parashar Dhapola, Rintu Kutum, Mohammed FaruqAbstract:Spinocerebellar ataxia type-12 (SCA12) is a neurological disorder that exhibits a unique progressive tremor/ataxia syndrome induced by triplet (CAG) repeat expansion in 5 prime UTR of PPP2R2B. SCA12 is one of the most prominent SCA-subtype in India and till date no appropriate disease models have been described. Our aim was to establish human iPSC derived neuronal cell lines of SCA12 and study transcriptomic level alterations induced by CAG expansion. For translational application, peripheral blood transcriptomics of SCA12 patients was also performed. Lymphoblastoid cell lines of three SCA12 patients were reprogrammed to iPSCs and then re-differentiated into pan-neuronal lineage. RNA-sequencing based comparative transcriptomics was performed for disease and control cell lineages. Microarray based transcriptomic profiling of peripheral blood of SCA12 patients was performed in a case/control (n=15/9) design. We have successfully created human neuronal cell lines of SCA12 patient as exhibited by their molecular profiling. Differential expression analysis of RNA-Seq data has shown enrichment for type-I interferon signaling and other relevant cellular processes in SCA12-neurons. At the splice-isoform level, we observed an upregulation of expanded CAG containing non-coding transcript of PPP2R2B. Peripheral blood transcriptomics analysis and targeted validation of RNA-Seq data has allowed us to identify inflammatory signatures as potential markers of molecular pathology in SCA12. Our study has allowed us to establish first iPSC based neuronal cell lines of SCA12. We have identified pro-inflammatory signatures in SCA12-neurons suggestive of a dsRNA mediated activation of interferon signaling and that corroborates with the emerging evidence of neuronal atrophy due to neuro-inflammation in common neurodegenerative diseases. This study involved development of an iPSCs derived neuronal cells of SCA12 and look through signatures of neurodegeneration by whole RNA sequencing. This model sheds light upon key role of RNA mediated induced response in Interferon signaling for neurodegeneration.
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Generation of three spinocerebellar ataxia type-12 patients derived induced pluripotent stem cell lines (IGIBi002-A, IGIBi003-A and IGIBi004-A).
Stem cell research, 2018Co-Authors: Deepak Kumar, Achal K. Srivastava, Ashaq Hussain, Mitali Mukerji, Odity Mukherjee, Mohammed FaruqAbstract:Abstract Spinocerebellar ataxia type-12 (SCA12) is a neurological disorder caused due to triplet (CAG) repeat expansion in 5' UTR of PPP2R2B. It is one of the most prominent SCA-subtype in Indian population and till date no patient specific models have been described. Human-induced-pluripotent-stem cell (HiPSC) based disease modelling has become the next generation tool for studying various human pathologies. In the present study we established three SCA12 patient specific iPSC lines. All the generated lines have shown pluripotency markers, normal karyotype, in-vitro three germ layers differentiation potential, vector clearance, SCA12 mutation, parental genomic identity and contamination free culture.
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Clinical behaviour of spinocerebellar ataxia type 12 and intermediate length abnormal CAG repeats in PPP2R2B
Brain : a journal of neurology, 2016Co-Authors: Achal K. Srivastava, Amit Takkar, Ajay Garg, Mohammed FaruqAbstract:Spinocerebellar ataxia type 12 (SCA12) is a rare neurodegenerative disorder caused by CAG repeat expansion in the PPP2R2B gene. Previously, the causal length of CAG repeats ascribed to SCA12 was more than 51; however, a few reports have also described unusual occurrence of CAG repeat length 36–51 repeats among patients of different geographical population, with atypical clinical association. From our systematic search for SCA12 in a genetic screening programme, we have identified a large number of SCA12 cases. In this study, we specifically describe the clinical behaviour of 18 patients who harbour CAG repeats in the range of 43–50 and compare their clinical behaviour with patients carrying typical pathogenic threshold length of 51 CAG repeats. Unsurprisingly, we observed that the clinical characteristics were similar to those of typical SCA12 phenotype, with large variability in the age at onset. Radiologically, we observed a variable degree of cerebro-cerebellar degeneration along with white matter changes that do not correlate with the disease severity. We define a new pathogenic threshold of CAG-43 to be pathogenic for SCA12 diagnosis and also describe the clinical profiles of two biallelic CAG expansion carriers. We also propose that SCA12 might not be that restricted in terms of occurrence in other geographical or ethnic populations, as it was previously presumed to be. * Abbreviations : ICARS = : International Cooperative Ataxia Rating Scale IpA = : intermediate pathogenic CAG alleles (43–50) PA = : typical pathogenic length of CAG alleles (51) SCA12 = : spinocerebellar ataxia type 12
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Identification and quantification of differentially expressed proteins in plasma of spinocerebellar ataxia type 12.
Neuroscience research, 2012Co-Authors: Vishnu Swarup, Achal K. Srivastava, Moganty R. RajeswariAbstract:Spinocerebellar ataxia 12 (SCA12) is a unique dominant type of ataxia characterized by early and prominent action tremors, memory deficit, neuropathy, dysarthria, etc. The expansion of DNA triplet (CAG) repeats in 5'UTR of PPP2R2B gene appears to be the cause for the pathogenesis of the neurodegenerative disorder, SCA12. The objective of the current study was to identify the aberrantly expressed plasma proteins for their potential application in therapy or diagnosis/prognosis of SCA12. Sixty-two clinically suspected patients were assessed using International Co-operative Ataxia Rating Scale (ICARS) and genetic confirmation was done using PCR followed by DNA sequencing. Twenty patients who were genetically confirmed were included in the study. 2D-DIGE analyses of plasma proteins of SCA12 patients revealed 14 differentially expressed protein spots, which were confirmed as nine proteins by LC-MS/MS. The 6 downregulated and 3 upregulated proteins are known to have physiological role in transport (thyroxin and retinol to brain), lipid metabolism, memory, scavenging of free haemoglobin, etc. Altered expression of some of the proteins of interest, transthyretin, haptaglobin, apolipoprotein C-II, apolipoprotein C-III are indicative of clinical manifestations such as neuropathy, cognitive impairment and altered lipid metabolism in SCA12.
Elizabeth O'hearn - One of the best experts on this subject based on the ideXlab platform.
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Neuropathology and Cellular Pathogenesis of Spinocerebellar Ataxia Type 12.
Movement disorders : official journal of the Movement Disorder Society, 2015Co-Authors: Elizabeth O'hearn, Hyon S. Hwang, Susan E. Holmes, Dobrila D. Rudnicki, Daniel W. Chung, Ana I. Seixas, Rachael L. Cohen, Christopher A. Ross, John Q. Trojanowski, Olga PletnikovaAbstract:Objective SCA12 is a progressive autosomal-dominant disorder, caused by a CAG/CTG repeat expansion in PPP2R2B on chromosome 5q32, and characterized by tremor, gait ataxia, hyperreflexia, dysmetria, abnormal eye movements, anxiety, depression, and sometimes cognitive impairment. Neuroimaging has demonstrated cerebellar and cortical atrophy. We now present the neuropathology of the first autopsied SCA12 brain and utilize cell models to characterize potential mechanisms of SCA12 neurodegeneration. Methods A fixed SCA12 brain was examined using gross, microscopic, and immunohistochemical methods. The effect of the repeat expansion on PPP2R2B Bβ1 expression was examined in multiple cell types by transient transfection of constructs containing the PPP2R2B Bβ1 promoter region attached to a luciferase reporter. The neurotoxic effect of PPP2R2B overexpression was examined in transfected rat primary neurons. Results Neuropathological investigation revealed enlarged ventricles, marked cerebral cortical atrophy and Purkinje cell loss, less-prominent cerebellar and pontine atrophy, and neuronal intranuclear ubiquitin-positive inclusions, consistent with Marinesco bodies, which did not stain for long polyglutamine tracts, alpha-synuclein, tau, or transactive response DNA-binding protein 43. Reporter assays demonstrated that the region of PPP2R2B containing the repeat functions as a promoter, and that promoter activity increases with longer repeat length and is dependent on cell type, repeat sequence, and sequence flanking the repeat. Overexpression of PPP2R2B in primary cortical neurons disrupted normal morphology. Conclusions SCA12 involves extensive, but selective, neurodegeneration distinct from Alzheimer's disease, synucleinopathies, tauopathies, and glutamine expansion diseases. SCA12 neuropathology may arise from the neurotoxic effect of repeat-expansion–induced overexpression of PPP2R2B. © 2015 International Parkinson and Movement Disorder Society
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Spinocerebellar Ataxia Type 12
Handbook of clinical neurology, 2012Co-Authors: Elizabeth O'hearn, Susan E. Holmes, Russell L. MargolisAbstract:SCA12 is a late-onset, autosomal dominant, slowly progressive disorder. Action tremor is the usual presenting sign. Subsequent development of ataxia and hyperreflexia suggests spinocerebellar ataxia. In the index SCA12 kindred, which resides in North America and is of German ancestry, parkinsonism, anxiety, depression, and cognitive dysfunction are not uncommon. SCA12 is linked to a CAG repeat expansion mutation in exon 7 of PPP2R2B, a gene that encodes Bβ, a regulatory subunit of protein phosphatase 2A (PP2A). CAG repeats number 7-28 in normal individuals and 55-78 in SCA12 patients. The mechanism by which this mutation leads to SCA12 has not been determined. The CAG expansion in PPP2R2B has promoter function in vitro. CAG length correlates with increased Bβ expression. There is no evidence that this CAG expansion results in polyglutamine production. In addition to the North. American SCA12 kindred, multiple SCA12 families have been found in Northern India that are not related to the index SCA12 kindred. SCA12 has been reported, rarely, in Singapore and China. Action tremor, anxiety, and depression in SCA12 have responded to usual treatments for these disorders. SCA12 may be considered in patients who present with action tremor and later develop signs of cerebellar and cortical dysfunction.
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Genetic Instabilities and Neurological Diseases (Second Edition) - CHAPTER 31 – Spinocerebellar Ataxia Type 12
Genetic Instabilities and Neurological Diseases, 2006Co-Authors: Susan E. Holmes, Elizabeth O'hearn, Hyon S. Hwang, Christopher A. Ross, Natividad Cortez-apreza, S. Strack, Russell L. MargolisAbstract:This chapter focuses on spinocerebellar ataxia type 12 (SCA12) caused by a CAG repeat expansion in PPP2R2 that encodes one of the brain-specific regulatory subunits of the trimeric phosphatase PP2A. SCA12 is the second most common SCA in India, accounting for approximately 8% of dominant ataxia cases; however, it is a rare disease in all other populations studied to date, having been found in only the single North American index pedigree. Clinically, SCA12 is the only inherited SCA that has action tremor as the presenting and most common sign. The SCA12 CAG repeat is found in the probable promoter region of the PPP2R2B variant encoding the predominant isoform (Bβ1) of the Bβ regulatory subunit. Repeat expansion appears to drive increased transcription from this promoter, suggesting that disease pathogenesis may involve overexpression of Bβ1 and lead to altered activity of PP2A, a ubiquitous enzyme implicated in multiple cellular processes including apoptosis. The SCA12 repeat is also within the intronic sequence of multiple alternately spliced transcripts with alternate promoters that encode additional Bβ isoforms, including Bβ2, which targets PP2A to the mitochondria, and promotes apoptosis when overexpressed. Pathogenesis may also involve an expansion-induced shift in splicing or choice of promoters, leading to an increase in expression of Bβ2.
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Evidence of a Common Founder for SCA12 in the Indian Population
Annals of Human Genetics, 2005Co-Authors: Samira Bahl, Elizabeth O'hearn, Susan E. Holmes, Russell L. Margolis, K. Virdi, Uma Mittal, Mohinder Pal Sachdeva, A.k. Kalla, S. Jain, Achal K. SrivastavaAbstract:Spinocerebellar ataxia type 12 (SCA12) is an autosomal dominant cerebellar ataxia associated with the expansion of an unstable CAG repeat in the 5' region of the PPP2R2B gene on chromosome 5q31-5q32. We found that it accounts for approximately 16% (20/124) of all the autosomal dominant ataxia cases diagnosed in AIIMS, a major tertiary referral centre in North India. The length of the expanded allele in this population ranges from 51-69 CAG triplets. Interestingly, all the affected families belong to an endogamous population, which originated in the state of Haryana, India. We identified four novel SNPs and a dinucleotide marker spanning approximately 137 kb downstream of CAG repeat in the PPP2R2B gene. Analysis of 20 Indian SCA12 families and ethnically matched normal unrelated individuals revealed one haplotype to be significantly associated with the affected alleles (P= 0.000), clearly indicating the presence of a common founder for SCA12 in the Indian population. This haplotype was not shared by the American pedigree with SCA12. Therefore, the SCA12 expansion appears to have originated at least twice.
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Why is SCA12 different from other SCAs
Cytogenetic and genome research, 2003Co-Authors: Susan E. Holmes, Elizabeth O'hearn, R L MargolisAbstract:Spinocerebellar ataxia type 12 (SCA12), now described in European-American and Asian (Indian) pedigrees, is unique among the SCAs from clinical, pathological, and molecular perspectives. Clinically, the distinguishing feature is early and prominent action tremor with variability in other signs. Pathologically, brain MRIs also suggest variability, with prominent cortical as well as cerebellar atrophy. Genetically, SCA12 is caused by a CAG repeat expansion that does not encode polyglutamine; we speculate that the mutation may affect expression of the gene PPP2R2B, which encodes a brain-specific regulatory subunit of the protein phosphatase PP2A.
Wanda Baerdubowska - One of the best experts on this subject based on the ideXlab platform.
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the negative regulators of wnt pathway dach1 dkk1 and wif1 are methylated in oral and oropharyngeal cancer and wif1 methylation predicts shorter survival
Tumor Biology, 2015Co-Authors: Jarosław Paluszczak, Reidar Grenman, Joanna Sarbak, Magdalena Kostrzewskapoczekaj, Katarzyna Kiwerska, Malgorzata Jarmuzszymczak, Daniela Mielcarekkuchta, Wanda BaerdubowskaAbstract:The deregulation of Wnt signaling has recently emerged as one of the drivers of head and neck cancers. This is frequently related to the methylation of several antagonists of this pathway. This study aimed at the assessment of the profile of methylation of Wnt pathway antagonists and the determination of the prognostic value of the methylation of selected genes in oral carcinomas. The methylation of DACH1, DKK1, LKB1, PPP2R2B, RUNX3, SFRP2, and WIF-1 was analyzed in 16 oral squamous cell carcinoma cell lines using the methylation-specific polymerase chain reaction. The methylation of selected genes was further analyzed in tumor sections from 43 primary oral carcinoma patients. The analysis of oral carcinoma cell lines showed very frequent methylation of SFRP2 and WIF-1 and also a less frequent methylation of DACH1 and DKK1. On the other hand, RUNX3 was methylated only in one cell line, while LKB1 and PPP2R2B were not methylated in any of the cell lines. The biallelic methylation of DKK1 correlated with the low level of expression of this gene. Further evaluation of the methylation of DACH1, DKK1, and WIF1 in a clinical patient group confirmed the frequent methylation of WIF1 and intermediate or low frequency of methylation of DACH1 or DKK1, respectively. Importantly, the methylation of WIF-1 correlated with shorter survival in oral cancer patients. Overall, the methylation of the antagonists of Wnt pathway is frequently detected in oral squamous cell carcinomas. The methylation of WIF1 may be considered a prognostic marker in oral cancers.